* Beginning 24 hours after the loading dose
In preterm infants with insufficient clinical response to the recommended loading dose, a second loading dose of 10 -20 mg/kg maximum may be given after 24 hours.
Higher maintenance doses of 10 mg/kg body weight could be considered in case of insufficient response, taking into account the potential for accumulation of caffeine due to the long half- life in premature neonates and the progressively increasing capacity to metabolise caffeine in relation to post-menstrual age (see section 5.2). Where clinically indicated, caffeine plasma levels should be monitored. The diagnosis of apnoea of prematurity may need to be reconsidered if patients do not respond adequately to a second loading dose or maintenance dose of 10 mg/kg/day (see section 4.4).
When given intravenously, caffeine citrate should be administered by controlled intravenous infusion, using a syringe infusion pump or other metered infusion device only. Caffeine citrate can be either used without dilution or diluted in sterile solutions for infusion such as glucose 50 mg/ml (5%), or sodium chloride 9 mg/ml (0.9%) or calcium gluconate 100 mg/ml (10%) immediately after withdrawal from the ampoule (see section 6.6).
Routine monitoring of plasma caffeine levels is not necessary in the majority of preterm infants. However, plasma concentrations of caffeine may need to be monitored periodically throughout treatment in cases of incomplete clinical response or signs of toxicity.
Additionally, doses may need to be adjusted according to medical judgment following routine monitoring of caffeine plasma concentrations in at risk situations such as:
− very premature infants (< 28 weeks gestational age and/or body weight <1000 g) particularly when receiving parenteral nutrition
− infants with hepatic and renal impairment (see sections 4.4 and 5.2)
− infants with seizure disorders
− infants with known and clinically significant cardiac disease
− infants receiving co-administration of medicinal products known to interfere with caffeine metabolism (see section 4.5)
− infants whose mothers consume caffeine while providing breast milk for feeding.
It is advisable to measure baseline caffeine levels in:
− infants whose mothers may have ingested large quantities of caffeine prior to delivery (see section 4.4)
− infants who have previously been treated with theophylline, which is metabolized to caffeine.
Caffeine has a prolonged half-life in premature newborn infants and there is potential for accumulation which may necessitate monitoring infants treated for an extended period (see section 5.2).
Blood samples for monitoring should be taken just before the next dose in the case of therapeutic failure and 2 to 4 hours after the previous dose when suspecting toxicity.
Although a therapeutic plasma concentration range of caffeine has not been determined in the literature, caffeine levels in studies associated with clinical benefit ranged from 8 to 30 mg/l and no safety concerns have normally been raised with plasma levels below 50 mg/l.
Caffeine citrate can be administered by intravenous infusion and by the oral route. The product must not be a